The research carried out in the subject application was supported in part by grants from the University of Texas El Paso University Research Institute, Grant No. 14-5078-2551 and University of Texas El Paso Border Health Research, Grant No. 19-2750-5057.
Combinatorial chemistry is a critical tool in both chemical biology and drug discovery. The importance of combinatorial chemistry is increasing as the demand for libraries of small organic compounds grows. More recently, these libraries have become particularly useful to further the advances in fields such as chemical genetics, genomics and proteomics. Because of this demand, there is a need to develop more efficient strategies for the high-fidelity solid phase construction of chemical libraries, especially those that resemble natural products or known therapeutic compounds.
Lead compounds with the potential to progress as viable drug candidates have been identified from compound libraries using several strategies. Viable drug candidate strategies include rapid screening of large diverse collections, thematic libraries, project-directed libraries, and three-dimensional molecular models using corporate-derived drug databases. These strategies have also been used to identify potential therapeutic candidates then evaluated in controlled clinical trials.
More recent interest has developed in applying combinatorial chemistry techniques to the study of benzene and many of its derivatives. Compounds using traditional organic chemistry as well as solid phase organic chemistry have been isolated and used industrially as biologic reagents. Fused heterocyclic compounds are common in nature (e.g., purine) and are often biologically active and used as drugs to treat a wide variety of diseases. In addition, Fischer carbene complexes have been pursued in organic chemistry synthesis because of their strongly acidic hydrogens (ones alpha to the carbene carbon), strong electron-withdrawing power, and ease of deprotonation. The strong electrophilic property of moieties such as Cr(CO)5 make them particularly useful in the synthesis of organic compounds as their deprotonation results in a metal “enolate” that is especially reactive with electrophilic reagents. The present invention exploits this property by using these moieties to prepare a whole new host of organic compound libraries that may serve as potential lead compounds.
Most recently, research has suggested that it may be possible to immobilize chromium carbene complexes with polymer-supported tripeptide and triphenyl phosphine. These complexes, however, remain limited in their ability to generate lead compounds as they are merely complexes formed in a series of reactions to create organic compounds with potential biological activity. To date, no one has described the use of polymer bound chromium (Cr) carbene complexes for the synthesis of any compound library for any reaction.
The present invention has met this need by creating active scaffolds and has also allows the scaffolds to include a one-step oxidation and cleavage process that is desirable for high throughput and parallel processing of potential biologically active compounds. The approach centers on linking the carbene complex directly onto the solid support through the oxygen of the carbene. The process allows for subsequent modifications of an attached phenol that leads to a large diversity of products. More importantly, the present invention is unique from the earlier attempts to create a class of biologically active scaffolds for combinatorial and solid phase organic chemistry.
The benefits of the present invention include the generation of a new class of biologically active scaffolds that encompass essential features of combinatorial chemistry. The present invention is able to both use the microenvironment of the solid support for synthesis of the desired compound and as reactant. The microenvironment may serve as both solid-phase reagent and a traceless linker. In addition, potentially biologically active compounds are cleaved off the solid support in a one-step parallel process.